MECHANISMS OF REGULATION OF CARDIAC AFFERENTS

描述(由申请者提供)：来自心脏的反应 心肌梗死时心血管系统的重要调节作用 缺血和再灌流。回应可能包括深刻的改变 血流动力学功能表现为反射性心血管抑制 在刺激迷走神经传入末梢或兴奋时激活 交感神经(脊髓)传入。从而刺激心脏的感觉神经 可引起低血压、心律失常、恶心和呕吐(迷走神经传入) 或心绞痛、高血压和快速性心律失常(交感传入)。有限 交感神经心脏激活机制的信息是可用的 也作为心脏伤害性感受器的传入，尽管我们最近的数据 猫的研究表明，与腺苷相反，活性氧物种(ROS)， 尤其是羟基自由基、激动素、质子(H+)和前列腺素 重要的刺激因素。因为抑制这些刺激及其受体 相互作用并不能完全消除这些感官传入的反应 缺血的结局，我们怀疑其他代谢或机械刺激起作用 在它们的激活和刺激之间的相互作用中发挥作用。 我们提出了一系列研究来检验血小板是一种 5羟色胺(5羟色胺)和组胺的来源。活化的血小板释放5-羟色胺 组胺，通过5HT3和H1，可能还有H2受体， 分别在缺血和缺血时刺激心脏交感神经传入 再灌流。这两种假定的化学物质和其他已知化学物质之间的相互作用 将对调解人进行考察。此外，二酰甘油/蛋白质的作用 激酶C(PKC)和环磷酸腺苷(CAMP)/蛋白激酶A(PKA) 组胺对缺血敏感心脏作用的信号系统 交感传入将被定义。我们将使用高效液相色谱来 测量血液和组织中介质的产量。单单位传入 将记录电活动和选择性药理受体 阻断或酶途径抑制将被用来评估其作用 每个潜在的化学介体。化学敏感、机械敏感和双峰 无髓纤维和有髓纤维的末梢将通过 一系列化学和机械挑战，后者由 血流动力学测量和局部心肌变形。建议数 因此，研究将确定心脏交感神经终止的机制 在缺血和再灌流期间被激活。这些信息将提供 对心绞痛和潜在危险有更好了解的医生 交感-兴奋性心脏反射和可能的治疗方法 旨在限制这些影响患者发病率和死亡率的事件 在心肌缺血期间。

DESCRIPTION (provided by the applicant): Reflexes from the heart play an important role in regulation of the cardiovascular system during myocardial ischemia and reperfusion. Responses can include profound alterations in hemodynamic function manifested as either reflex cardiovascular depression during stimulation of vagal afferent endings or excitation with activation of sympathetic (spinal) afferents. Stimulation of sensory nerves in the heart thus can cause hypotension, bradyarrhythmias, nausea and vomiting (vagal afferents) or angina, hypertension and tachyarrhythmias (sympathetic afferents). Limited information is available on mechanisms of activation of sympathetic cardiac afferents that also function as cardiac nociceptors, although our recent data in cats indicate that, in contrast to adenosine, reactive oxygen species (ROS), especially hydroxyl radicals ('OH), kinins, protons (H+) and prostaglandins are important stimuli. Because inhibition of these stimuli and their receptor interactions does not fully eliminate the response of these sensory afferent endings to ischemia, we suspect that other metabolic or mechanical stimuli play a role in their activation and that interactions between stimuli are present. We propose a series of studies to test the hypotheses that platelets are a source of serotonin (5HT) and histamine. Activated platelets release serotonin and histamine that, through 5HT3 and H1 and possibly H2 receptors, respectively, stimulate cardiac sympathetic afferents during ischemia and reperfusion. Interactions between these two putative and other known chemical mediators will be explored. In addition, the role of diacylglycerol/protein kinase C (PKC) and cyclic adenosine monophosphate (cAMP)/protein kinaseA (PKA) signaling systems in histamine's action on ischemically sensitive cardiac sympathetic afferents will be defined. We will employ liquid chromatography to measure the production of mediators in blood and tissue. Single unit afferent electrical activity will be recorded and selective pharmacological receptor blockade or enzymatic pathway inhibition will be used to evaluate the role of each potential chemical mediator. Chemosensitive, mechanosensitive and bimodal endings of unmyelinated and myelinated fibers will be identified through a series of chemical and mechanical challenges, the latter assessed by hemodynamic measurement and regional myocardial deformation. The proposed studies therefore will define mechanisms by which cardiac sympathetic endings are activated during ischemia and reperfusion. Such information will provide physicians with a better understanding of angina and potentially dangerous sympathoexcitatory cardiac reflexes and may suggest therapeutic approaches designed to limit these events that impact patient morbidity and mortality during myocardial ischemia.